Controlled release pharmaceutical formulation containing venlafaxine

ABSTRACT

A solid controlled release pharmaceutical formulation for once daily administration comprises a core comprising venlafaxine, polyvinylpyrrolidone, a low viscosity hydrophilic polymer and a high viscosity hydrophilic polymer, and a polymeric coating comprising a water high permeable polymer, and a water low permeable polymer. The invention further relates to a process for the preparation of a solid controlled release pharmaceutical formulation comprising the steps of dissolving venlafaxine and ployvinylpyrrolidone in an organic solvent, applying the resulting solution onto low viscosity polymer, homogeneously mixing the obtained granulate with a high viscosity polymer, and compressing the granulate to obtain a core which is then coated with a polymeric coating comprising a water high permeable polymer and a water low permeable polymer.

This invention relates to a controlled release pharmaceuticalformulation for once daily administration, in particular to a controlledrelease pharmaceutical formulation of venlafaxine.

Venlafaxine, chemically named (±)1-[2-(dimethylamino)-1(4-methoxyphenyl)ethyl]-cyclohexanol, is anantidepressant disclosed in EP-A-0 112 669. Presently venlafaxinehydrochloride is administered to adults as conventional immediaterelease tablets or as 24 hour extended-release multiparticulatecapsules.

Venlafaxine hydrochloride is very soluble in water. It is known that itis very difficult to develop a pharmaceutical form with a very slowdissolution rate of freely soluble drug. Besides that, venlafaxinehydrochloride is polymorphic, so dissolution is dependent also onpolymorphic form and particle size of particular polymorphic form.Therefore, it is a special task to develop such a pharmaceuticalformulation that would sustain and control the dissolution of freelysoluble drug over 24 hour period.

EP-A-0 797 991 and WO 99/22724 disclose encapsulated venlafaxineextended release dosage formulation of venlafaxine hydrochloride, whichprovides in a single dose, a therapeutic blood serum level over a twentyfour hour period. Gelatine capsules are filled with film coatedspheroids containing venlafaxine hydrochloride. EP-A-0 797 991 statesthat numerous attempts to produce extended release tablets by hydrogeltechnology proved to be fruitless because the compressed tablets wereeither physically unstable (poor compressibility or capping problems) ordissolved too rapidly in dissolution studies. Typically, the tabletsprepared as hydrogel sustained release formulations gave 40-50%dissolution at 2 hours, 60-70% dissolution at 4 hours and 85-100%dissolution at 8 hours (EP-A-0 797 991).

WO 94/27589 and WO 01/37815 describe osmotic dosage forms containingvenlafaxine hydrochloride.

The object of the invention is to provide an improved solid controlledrelease pharmaceutical formulation containing venlafaxine and a processfor the preparation thereof. This object is achieved for example by thecombination of the features in each of the independent claims 1 and 26.Preferable embodiments of the invention are defined in the dependentclaims.

The pharmaceutical formulation of the present invention comprises forexample a core consisting of an active drug which may be advantageouslyin amorphous form, polyvinylpyrrolidone, a combination of twohydrophilic polymers having different viscosities and optionally othercommonly used ingredients for solid dosage forms. The core is coatedwith a polymeric coating comprising a combination of two polymers havingdifferent water permeabilities. A plasticizer and other commonly usedingredients for film coating may be optionally added thereto.

A solid controlled release formulation according to a preferredembodiment of the present invention comprises for example a coreconsisting of venlafaxine, polyvinylpyrrolidone, a combination of twodifferent hydrophilic polymers preferably from the group of celluloseethers from which the first one may be a low viscosity cellulose etherand the second one may be a high viscosity cellulose ether, and othercommonly used ingredients for solid dosage forms. The core is coatedwith a polymeric coating comprising a combination of two differentpolymers from which the first one is water high permeable polymer andthe second one is water low permeable polymer. It is advantageous tofurther add a plasticizer and other commonly used ingredients for filmcoating.

Venlafaxine may be in a form of a pharmaceutically acceptable salt,preferably in a form of venlafaxine hydrochloride.

It was unexpected that once daily formulation of venlafaxinehydrochloride could be obtained using hydrogel technology based on acombination of low and high viscosity hydrophilic polymers although theactive substance is extremely hydrophilic and water soluble.

Controlled release of venlafaxine hydrochloride over 24 hours isachieved by a combination of two hydrophilic polymers of differentviscosity in the core and of two polymers of different waterpermeability in the coating.

The active ingredient stabilised with polymers is dispersed at themolecular level and has therefore always the same particle size and thesame specific surface area. Consequently, the dissolution rate is notpolymorph dependent but dependent solely on the combination and ratio oflow and high viscosity hydrophilic polymers in the core and oncombination and ratio of water high permeable and water low permeablepolymers in the coating.

The water soluble polymer polyvinylpyrrolidone prevents thecrystallisation of the active ingredient, simultaneously it is a carrierof the active ingredient in the coprecipitate. Polyvinylpyrrolidone witha K-value (relative viscosity of the compound in water solution withregard to water) preferably ranging from 10 to 95, more preferably inthe range from 24 to 32, with an average molecular weight preferablyranging from 2000 g/mol to 110000 g/mol, more preferably in the rangefrom 25000 g/mol to 50000 g/mol may be used. Polyvinylpyrrolidone ispreferably present in the formulation in the range from 5 to 40 wt %,more preferably from 10 to 20 wt %, with respect to the total weight ofthe formulation.

The low viscosity hydrophilic polymer acts as a carrier of the activeingredient which simultaneously inhibits its crystallisation in thecoprecipitate of venlafaxine hydrochloride and polyvinylpyrrolidone, andtogether with other ingredients it modifies the release of the activesubstance in such a way that it is sustained over 24 hour period.

The low viscosity hydrophilic polymer may preferably be present in aquantity from 10 to 70 wt %, more preferably from 20 to 50 wt %, withrespect to the total weight of the pharmaceutical formulation.

For providing a stable, preferably amorphous form of the activeingredient in the novel pharmaceutical formulation the required weightratio between the water soluble polymer polyvinylpyrrolidone and the lowviscosity hydrophilic polymer is preferably in the range from 10:1 to1:10, more preferably in the range from 1:3 to 3:1.

The combination of the carriers i.e. the water soluble polymerpolyvinylpyrrolidone and the low viscosity hydrophilic polymer has adouble effect and the advantage that it stabilises the amorphous form ofthe active ingredient and simultaneously modifies the release of theamorphous active ingredient in such a way that it is sustained,repeatable and independent of the amorphous or polymorphous form of theactive ingredient, its particle size and specific surface area.

The high viscosity hydrophilic polymer in combination with low viscosityhydrophilic polymer modifies the release of the active substance in sucha way that it is sustained over 24 hour period.

High viscosity hydrophilic polymer is present preferably in a quantityfrom 5 to 70 wt %, more preferably from 7 to 50 wt %, with respect tothe total weight of the pharmaceutical formulation.

A low viscosity and a high viscosity hydrophilic polymer can preferablybe selected from cellulose ethers selected from the group consisting ofmethylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, preferably hydroxyethylcellulose,hydroxypropylcellulose and hydroxymethylpropylcellulose. Combinationsmay also be used.

Particularly preferable cellulose ether is hydroxypropylmethylcellulose.A low viscosity hydroxypropylmethylcellulose is defined as one havingpreferably a molecular weight of 55,000 or less and viscosity of 800mPas or less. A high viscosity hydroxypropylmethylcellulose is definedas one preferably having a molecular weight of 60,000 or greater andviscosity of 1000 mPas or greater. Different types ofhydroxypropylmethylcellulose may be used. Relative rate of Viscosity %methoxyl % hydroxypropoxyl hydration mPas Type K 19-24 7-12 fastest 3,100, 4000, 15000, 10000 Type E 28-30 7-12 next 3, 5, 6, fastest 15, 50,4000 Type F 27-30  4-7,5 slower 50, 4000

For providing a sustained release of highly soluble amorphous activeingredient from a novel pharmaceutical formulation over 24 hour periodthe required ratio between the low viscosity and high viscosityhydrophilic polymer is preferably from 10:1 to 1:3, more preferably from6:1 to 1:2, in particular preferably from 3:1 to 1:1.

The core may also contain other usual ingredients useful in thepreparation of solid pharmaceutical forms such as fillers, binders,swelling excipients, glidants, lubricants etc. The core may contain oneor more fillers such as lactose, starch, saccharose, glucose,microcrystalline cellulose, mannitol, sorbitol, calcium hydrogenphosphate, aluminium silicate, sodium chloride. Further it may containone or more binders such as starch, gelatine, carboxymethylcellulose,polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, sodium alginate,microcrystalline cellulose etc.; one or-more disintegrants such asstarch, cross-linked sodium carboxymethylcellulose, cross-linkedpolyvinylpyrrolidone, sodium starch glycolate etc., one or more glidantssuch as magnesium stearate, calcium stearate, aluminium stearate,stearic acid, palmitic acid, cetanol, stearol, polyethylene glycols ofvarious molecular weights, talc, etc., one or more lubricants such asstearic acid, calcium, magnesium or aluminium stearate, siliconized talcetc.

The formulation contains in a preferred embodiment from 10 to 400 mg ofvenlafaxine, more preferably from 30 to 200 mg of venlafaxine,particularly preferably from 37,5 to 150 mg of venlafaxine. venlafaxineis in a form of pharmaceutically acceptable salt, more preferably asvenlafaxine hydrochloride.

The film coating comprises a combination of two different polymers fromwhich the first one is a water high permeable polymer and the second oneis a water low permeable polymer.

As a water high permeable polymers are considered polymers which aresoluble (suitably 3.3% or more, more suitably 5% or more, even moresuitably 10% or more, particularly suitably 50% or more and especiallysuitably 70% or more ) in water (e.g. hydroxypropylcellulose,hydroxypropylmethylcellulose, methylcellulose and hydroxyethylcellulose)or can achieve water permeability by swelling or salt formation (e.g.methacrylate aminoester copolymer, methylcellulose) or contain groupspermeable for water in a high proportion (suitably molar ratio of waterpermeable to water non-permeable groups is 1:30 or more) (e.g. highpermeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride).

As water low permeable polymers are considered polymers which areinsoluble in water, some in entire physiological pH (e.g.ethylcellulose) and some in acidic pH (e.g. cellulose acetate phthalate,methacrylic acid copolymers, polyvinyl acetate phthalate, celluloseacetate trimellitate, hydroxypropylmethylcellulose phthalate), orcontain groups permeable for water in a small proportion (suitably molarratio of water permeable to water non-permeable groups is 1:30 or less)(e.g. low permeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride).

Water high permeable polymer may preferably be selected frommethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, methacrylate aminoester copolymer, high permeablepoly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride,preferably hydroxypropylcellulose, hydroxypropylmethylcellulose,methylcellulose and high permeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride, mostpreferably from hydroxypropylcellulose, hydroxypropylmethylcellulose andhigh permeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride. Theselection of the water high permeable polymer should not be restrictedby these examples.

Water low permeable polymer may preferably be selected fromethylcellulose, cellulose acetate phthalate, methacrylic acidcopolymers, polyvinyl acetate phthalate, cellulose acetate trimellitate,hydroxypropylmethylcellulose phthalate and low permeablepoly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride,preferably ethylcellulose, hydroxypropylmethylcellulose phthalate,polyvinyl acetate phthalate and low permeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride, mostpreferably from ethylcellulose, hydroxypropylmethylcellulose phthalateand low permeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride. Theselection of the water low permeable polymer should not be restricted bythese examples.

The combinations of water high permeable and water low permeablepolymers may be selected in particular from, but not limited to,combination of hydroxypropylmethylcellulose andhydroxypropylmethylcellulose phthalate, hydroxypropylcellulose andhydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose andethylcellulose, hydroxypropylcellulose and ethylcellulose,hydroxypropylmethylcellulose and polyvinyl acetate phthalate,hydroxypropylcellulose and polyvinyl acetate phthalate, high permeablepoly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride and lowpermeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride,preferably hydroxypropylmethylcellulose and hydroxypropylmethylcellulosephthalate, hydroxypropylcellulose and ethylcellulose,hydroxypropylmethylcellulose and ethylcellulose, high permeablepoly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride and lowpermeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride.

The ratio between the water high permeable and water low permeablepolymers is preferably from 10:1 to 1:5, more preferably from 6:1 to1:4, particularly preferably from 3:1 to 1:3.

The coating is preferably present in the formulation in the range from 1to 15 wt %, more preferably from 2 to 10 wt %, with respect to the totalweight of the formulation.

The coating may also contain other usual ingredients useful in thepreparation of film coated solid dosage forms such as plasticizers,fillers, antisticking agents, antifoams, colorants etc.

The coating may contain one or more plasticizers such acetyl tributylcitrate, acetyl thriethyl citrate, acetylated fatty acid glycerides,castor oil, dibutyl phthalate, diethyl phthalate, diethyl sebacate,dibutyl sebacate, dimethyl phthalate, glycerol, glycerol monostearate,glycelyl triacetate, polyethylene glycols,polyoxyethylene/polyoxypropylene copolymers, propylene glycol, tributylcitrate, triethyl citrate. Further it may contain one or more fillerssuch as lactose, polydextrose and maltodextrin; one or more antistickingagents such as talc, magnesium stearate, calcium stearate, etc., one ormore antifoams such as dimethylpolysiloxane, etc., one or more colorantssuch as titanium dioxide, iron oxides, lakes, etc.

A combination of amorphous form of an active ingredient in thecoprecipitate with water soluble polyvinylpyrrolidone and a combinationof low viscosity and high viscosity hydrophilic polymer in the core anda combination of water high permeable and water low permeable polymer inthe coating, prepared in a certain ratio between the single componentsof the formulation according to the process of the invention, which issimple and technologically as well as economically acceptable, hashitherto not been described in the literature. The granulation of anactive ingredient, the water soluble polymer polyvinylpyrrolidone and acombination of low viscosity and high viscosity hydrophilic polymer andother ingredients suitable for preparation of solid pharmaceutical formshas good compressibility, so prepared tablets are firm, have lowfriability and together with a combination of water high permeable andwater low permeable polymer in the coating make possible a sustainedrelease of the amorphous active ingredient from pharmaceuticalformulation over 24 hour period. Due to the preferable amorphous form ofthe active ingredient, the release rate of the active ingredient is notdependent on polymorphic form and particle size of active ingredient butsolely on the combination and ratio of low and high viscosityhydrophilic polymers in the core and on combination and ratio of waterhigh permeable and water low permeable polymer in the coating.

The above object can also be achieved by a process defined in claim 26.For example in the first step of the preparation of a pharmaceuticalformulation according to the invention an active ingredient and thewater soluble polymer polyvinylpyrrolidone are dissolved in an organicsolvent at a temperature e.g. from 20 to 60° C., and preferably in afluid bed granulator. The obtained solution is applyed, preferablysprayed onto a low viscosity hydrophilic polymer such as e.g. celluloseether in the fluid bed. As the active ingredient there can be used anamorphous form or a polymorphous form of the active ingredient which inthe process of coprecipitation according to the invention is convertedinto an amorphous form stabilised with water solublepolyvinylpyrrolidone and low viscosity hydrophilic polymer. Organicsolvents useful for this purpose can be selected from group of alcohols,ketones, esters, aliphatic hydrocarbons, halogenated hydrocarbons,cycloaliphatic, aromatic, heterocyclic solvents or mixtures thereof.Typical solvents can be ethanol, methanol, isopropyl alcohol, n-butylalcohol, acetone, diethyl ether, ethyl acetate, isopropyl acetate,methyl acetate, dichloromethane, chloroform, mixtures of these solventssuch as ethanol and acetone, methanol and acetone, dichloromethane andmethanol and mixtures thereof. If a polymorphous form of the activeingredient is chosen, it is in the process of the invention convertedinto an amorphous form which is stabilised with water soluble polymerpolyvinylpyrrolidone and low viscosity hydrophilic polymer. The obtainedgranulation is suitably regranulated through a sieve of mesh size 0.5 mmat room temperature.

The second step of the preparation of a pharmaceutical formulationaccording to the invention is, for example, conducted in such a mannerthat at room temperature the granulation obtained in the first step ishomogeneously blended with a high viscosity hydrophilic polymer andother usual adjuvants useful in the preparation of solid pharmaceuticalforms such as lactose, polyvinylpyrrolidone, cross-linkedpolyvinylpyrrolidone, starch, calcium hydrogen phosphate, calciumhydrogen carbonate, aluminium silicate, magnesium stearate, talc, orgenerally with fillers, binders, disintegrants, glidants, lubricantsetc.

The components are compressed to obtain a core which may suitably beprovided as tablets obtainable with known tableting machines. Thus it ispossible to prepare tablets with controlled release of an amorphousactive ingredient in a relatively simple and economical way.

In the third step of preparation of a pharmaceutical formulationaccording to the invention the obtained cores are, for example, filmcoated with a combination of water high permeable and water lowpermeable polymer. The coating can be performed using dispersion orcolloidal solution. Colloidal solution is prepared by dissolving thepolymers e.g. in an organic solvent, in mixtures of organic solvents orin mixtures thereof with water. As organic solvent ethanol, methanol,propan-2-ol, acetone, ethyl acetate, glacial acetic acid, glycols,dichloromethane, dimethyl formamide, dimethylsulfoxide, dioxanechloroform, toluene, methylene chloride, benzene, diaceton alcohol,ethoxyethyl acetate, ethylene glycol monoacetate, ethyl lactate,methoxyethyl acetate, β-methoxyethylene alcohol, methylethyl ketone canbe used.

Coating dispersion can be prepared either by mixing powders of polymersor other suitable ingredients in organic solvent or in combination oforganic solvent with water or by mixing and diluting aqueous dispersionof polymers with water.

In the second step plasticizer or a mixture of plasticizers may beoptionally added to the polymer colloidal solution or dispersion ofpolymers and then the suspension of colorants, antisticking agents,fillers, antifoams may be added. The coating can be performed by meansof known coating techniques in perforated coating pans. Thus it ispossible to prepare film coated tablets with sustained release of anamorphous active ingredient in a relatively simple and economical way.

The invention is illustrated, but in no way limited by the followingexamples:

EXAMPLE 1

Composition of one tablet Core: Venlafaxine hydrochloride 150 mgpolyvinylpyrrolidone K30 150 mg Hydroxypropylmethylcellulose MethocelF50P 450 mg Hydroxypropylmethylcellulose Methocel K100MP 70 mg Ludipress173 mg Talc 5 mg Mg stearate 2 mg Coating: HydroxypropylmethylcellulosePharmacoat 606 22,695 mg Hydroxypropylmethylcellulose phthalate 9,726 mgTriethyl citrate 2,598 mg Iron oxide yellow 0,788 mg Titanium dioxide2,373 mg Talc 0,324 mg

A batch of 800 tablets was prepared according to the followingprocedure:

Crystalline venlafaxine hydrochloride (120 g) and polyvinylpyrrolidoneK30 (120 g) (Kollidon 30, BASF; Plasdone K-30, ISP GAF) were dissolvedin ethanol (960 g) under intensive stirring at room temperature. Theformed solution (1200 g) was in a fluid bed at an inlet air temperaturefrom 70° C. to 85° C. sprayed onto hydroxypropylmethylcellulose (360 g)with a viscosity of 50 mPas (Methocel F50 premium, Dow Chemicals) andwith an average molecular weight of 19000 g/mol. The so preparedgranulation (600 g) was dried in a fluid bed and regranulated through asieve with mesh size 0.5 mm. To the granulation there were addedhydroxypropylmethylcellulose (56 g) with a viscosity of 100000 mPas(Methocel K100M premium, Dow Chemicals) and with an average molecularweight of 215000 g/mol, Ludipress (138.4 g) (93.4 wt % of lactosemonohydrate+3.2 wt % of polyvinylpyrrolidone K30 (Kollidon 30)+3.4 wt %of cross-linked polyvinylpyrrolidone (Kollidon CL, BASF Germany)), talc(4 g) and magnesium stearate (1.6 g) and they were homogeneously blendedat room temperature. The so prepared granulation with amorphousvenlafaxine hydrochloride was compressed into tablets using usualtableting machine so that tablets with a weight of 950 mg were obtained.

Hydroxypropylmethylcellulose (36.312 g) (Pharmacoat 606, Shin EtsuChemical Co. Japan) with a viscosity of 6 mPas,Hydroxypropylmethylcellulose phthalate (15.562 g) (HP-50, Shin EtsuChemical Co. Japan ) and triethyl citrate (4.150 g) (Morflex) weredissolved while stirring in a mixture of ethanol (410.774 g) and water(153.742 g), and then homogenised (Ultraturax, 30 min.) suspension oftitanium dioxide (3.797 g), iron oxide yellow (1.261 g) (Sicopharm 10,BASF) and talcum (0.518 g) in water (22.304 g) was added. Preparedsuspension was sprayed onto cores so that the film coating in a weightratio of about 4.8 wt. % regard to core was obtained. Tablets were alsopolished with talcum (0.563 g). Dissolution of the tablets. Apparatus:apparatus 2 (USP 23), 100 rpm Medium: 0-2 hours: artificial gastricjuice pH 1.2 2-24 hours: artificial intestinal juice pH 6.8 Temperature:37° C. Quantitative analysis: UV spectrophotometry, 273 nm

TABLE 1 Percentage of released venlafaxine vs. dissolution timeDissolution time Percentage of released (h) venlafaxine 1 13.2 2 22.0 332.1 4 39.6 6 51.3 8 60.7 10 68.5 12 74.9 14 80.3 16 84.6 18 88.2 2091.9 22 93.4 24 95.5

From the above table it is evident that venlafaxine dissolution issustained over 24 hour period.

EXAMPLE 2

Composition of one tablet Core: Venlafaxine hydrochloride 169,73 mgPolyvinylpyrrolidone K30 150 mg Hydroxypropylmethylcellulose MethocelF50P 380,27 mg Hydroxypropylmethylcellulose Methocel K100MP 150 mgLudipress 93 mg Talc 5 mg Mg stearate 2 mg Coating:Hydroxypropylcellulose Klucel EF 7,620 mg Ethylcellulose N7 17,780 mgTriethyl citrate 2,298 mg Titanium dioxide 7,756 mg Talc 2,546 mg

A batch of 800 tablets was prepared according to the followingprocedure: Tablet cores were prepared according to the same procedure asin Example 1.

Hydroxypropylcellulose (12.192 g) (Klucel EF, Hercules, Wilmington) withan average molecular weight of 60000 g/mol and a viscosity of 5-10 mPas, Ethylcellulose (28.448 g) (N7, Hercules, Wilmington) ethoxyl content48.0-49.5% and viscosity 5.6-8 mPas and triethyl citrate (3.677 g)(Morflex) were dissolved while stirring in ethanol (548.823 g), and thenhomogenised (Ultraturax, 30 min.) suspension of titanium dioxide (12.410g) and talcum (4.073 g) in ethanol (65.932 g) was added. Preparedsuspension was sprayed onto cores so that the film coating in a weightratio of about 4.0 wt. % regard to the core was obtained. Tablets werealso polished with talcum (0.563 g). Dissolution of the tablets.Apparatus: apparatus 2 (USP 23), 150 rpm Medium: 0-2 hours: artificialgastric juice pH 1.2 2-24 hours: artificial intestinal juice pH 6.8Temperature: 37° C. Quantitative analysis: UV spectrophotometry, 273 nm

TABLE 1 Percentage of released venlafaxine vs. dissolution timeDissolution time Percentage of released (h) venlafaxine 0.5 1.0 1 4.41.5 8.4 2 12.4 3 21.1 4 28.0 6 40.0 8 50.1 10 58.8 12 66.6 16 78.8 1883.3 20 87.1 24 92.0

From the above table it is evident that venlafaxine dissolution issustained over 24 hour period.

EXAMPLE 3

Composition of one tablet Core: Venlafaxine hydrochloride 169,73 mgPolyvinylpyrrolidone K30 150 mg Hydroxypropylmethylcellulose MethocelF50P 380,27 mg Hydroxypropylmethylcellulose Methocel K100MP 150 mgLudipress 93 mg Talc 5 mg Mg stearate 2 mg Coating:Hydroxypropylcellulose Klucel EF 10,160 mg Ethylcellulose N7 15,240 mgTriethyl citrate 2,298 mg Titanium dioxide 7,756 mg Talc 2,546 mg

A batch of 800 tablets was prepared according to the followingprocedure: Tablet cores were prepared according to the same procedure asin Example 1.

The coating of the tablet cores was performed according to the sameprocedure as an example 2 only a ratio of Hydroxypropylcellulose toEthylcellulose 1:1.5 was used. Dissolution of the tablets. Apparatus:apparatus 2 (USP 23), 150 rpm Medium: 0-2 hours: artificial gastricjuice pH 1.2 2-24 hours: artificial intestinal juice pH 6.8 Temperature:37° C. Quantitative analysis: UV spectrophotometry, 273 nm

TABLE 1 Percentage of released venlafaxine vs. dissolution timeDissolution time Percentage of released (h) venlafaxine 0.5 5.8 1 11.81.5 16.9 2 21.1 3 29.9 4 37.0 6 48.8 8 58.7 10 67.0 12 74.2 16 84.7 1888.2 20 91.0 24 94.1

EXAMPLE 4

Composition of one tablet Core: Venlafaxine hydrochloride 169,73 mgPolyvinylpyrrolidone K30 150 mg Hydroxypropylmethylcellulose MethocelF50P 380,27 mg Hydroxypropylmethylcellulose Methocel K100MP 250 mgLudipress 93 mg Talc 5 mg Mg stearate 2 mg Coating: Eudragit RL30D 2,450mg Eudragit RS30D 1,050 mg Triethyl citrate 0,700 mg Titanium dioxide3,815 mg Talc 5,404 mg Polyethylene glycol 6000 0,318 mgPolydimethylsiloxane 0,032 mg

A batch of 800 tablets was prepared according to the followingprocedure: Tablet cores were prepared according to the same procedure asin Example 1.

The coating of the tablet cores was performed according to the followingprocedure:

In the first step, polyethylene glycol (2.289 g) with a molecular weightof 5400-6600 (Clariant) was dissolved in part of the water (4.647 g).This solution and talcum (38.910 g), titanium dioxide (27.468 g),dimethylpolysiloxane (0.231 g) (Merck) were then stirred into part ofthe water (155.577 g) and homogenised (Ultraturrax, 30 min.). Toeliminate air bubbles stirring of pigment suspension was continuedovernight (approx. 12 hours).

The polymer dispersion were prepared from Eudragit RL 30D (58.800 g 30%aqueous dispersion of poly (ethylacrylate, methylmethacrylate)trimethylammoniumethylmethacrylate chloride), Eudragit RS 30D (25.200 g30% aqueous dispersion of poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride),triethyl citrate (5.040 g) and water (139.620 g) while mixing for 30min.

The pigment suspension and polymer dispersion were mixed for 20 minshortly before use.

So prepared suspension was sprayed onto cores so that the film coatingin a weight ratio of about 1.3 wt. % regard to the core was obtained.Dissolution of the tablets. Apparatus: apparatus 2 (USP 23), 150 rpmMedium: 0-2 hours: artificial gastric juice pH 1.2 2-24 hours:artificial intestinal juice pH 6.8 Temperature: 37° C. Quantitativeanalysis: UV spectrophotometry, 273 nm

TABLE 1 Percentage of released venlafaxine vs. dissolution timeDissolution time Percentage of released (h) venlafaxine 0.5 10.0 1 15.01.5 19.4 2 23.1 3 31.2 4 37.5 6 48.1 8 56.8 10 64.2 12 70.0 16 81.2 1885.1 20 88.2 24 92.7

From the above table it is evident that venlafaxine dissolution issustained over 24 hour period.

EXAMPLE 5

Composition of one tablet Core: Venlafaxine hydrochloride 169,73 mgPolyvinylpyrrolidone K30 150 mg Hydroxypropylmethylcellulose MethocelF50P 380,27 mg Hydroxypropylmethylcellulose Methocel K100MP 250 mgLudipress 93 mg Talc 5 mg Mg stearate 2 mg Coating:Hydroxypropylcellulose Klucel EF 12,700 mg Ethylcellulose N7 12,700 mgTriethyl citrate 2,298 mg Titanium dioxide 7,756 mg Talc 2,546 mg

A batch of 800 tablets was prepared according to the followingprocedure: Tablet cores were prepared according to the same procedure asin Example 1.

The coating of the tablet cores was performed according to the sameprocedure as an example 2 only a ratio of hydroxypropylcellulose toethylcellulose 1:1 was used. Dissolution of the tablets. Apparatus:apparatus 2 (USP 23), 150 rpm Medium: 0-2 hours: artificial gastricjuice pH 1.2 2-24 hours: artificial intestinal juice pH 6.8 Temperature:37° C. Quantitative analysis: UV spectrophotometry, 273 nm

TABLE 1 Percentage of released venlafaxine vs. dissolution timeDissolution time Percentage of released (h) venlafaxine 0.5 8.2 1 13.51.5 18.1 2 22.0 3 30.6 4 37.3 6 48.5 8 57.9 10 65.7 12 72.6 16 83.3 1887.3 20 90.4 24 94.2

From the above table it is evident that venlafaxine dissolution issustained over 24 hour period.

1. A solid controlled release pharmaceutical formulation for once dailyadministration comprising a core comprising venlafaxine,polyvinylpyrrolidone, a low viscosity hydrophilic polymer and a highviscosity hydrophilic polymer; and a polymeric coating comprising awater high permeable polymer, and a water low permeable polymer.
 2. Theformulation of claim 1 wherein venlafaxine is in a form of venlafaxinehydrochloride.
 3. The formulation of claim 1 wherein venlafaxine is inamorphous form.
 4. The formulation of claim 1 wherein the amount ofvenlafaxine is from 10 to 400 mg.
 5. The formulation of claim 1 whereinthe amount of venlafaxine is from 37.5 to 150 mg.
 6. The formulation ofclaim 1.wherein the amount of venlafaxine is 75 mg.
 7. The formulationof claim 1 wherein the amount of venlafaxine is 150 mg.
 8. Theformulation of claim 1 wherein the low viscosity hydrophilic polymer andthe high viscosity hydrophilic polymer in the core are selected fromcellulose ethers.
 9. The formulation of claim 1 wherein the lowviscosity hydrophilic polymer and the high viscosity hydrophilic polymerin the core are selected from the group consisting of methylcellulose,ethylcellulose, hydroxyethylcellulose, propylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose orcarboxymethylcellulose.
 10. The formulation of claim 1 wherein the lowviscosity hydrophilic polymer and the high viscosity hydrophilic polymerin the core are a low viscosity hydroxypropylmethylcellulose and a highviscosity hydroxypropylmethylcellulose.
 11. The formulation of claim 1wherein the ratio between polyvinylpyrrolidone and the low viscosityhydrophilic polymer in the core is from 10:1 to 1:10.
 12. Theformulation of claim 1 wherein the ratio between polyvinylpyrrolidoneand the low viscosity hydrophilic polymer in the core is from 1:3 to3:1.
 13. The formulation of claim 1 wherein the ratio between the lowviscosity hydrophilic polymer and the high viscosity hydrophilic polymerin the core is from 10:1 to 1:3.
 14. The formulation of claim 1 whereinthe ratio between the low viscosity hydrophilic polymer and the highviscosity hydrophilic polymer in the core is from 3:1 to 1:1
 15. Theformulation of claim 1 wherein the water high permeable polymer in thecoating is selected from the group consisting of methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, methacrylate aminoester copolymer, high permeablepoly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride.
 16. Theformulation of claim 1 wherein the water high permeable polymer in thecoating is selected from the group consisting of hydroxypropylcellulose,hydroxypropylmethylcellulose and high permeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride.
 17. Theformulation of claim 1 wherein the water low permeable polymer in thecoating is selected from ethylcellulose, cellulose acetate phthalate,methacrylic acid copolymers, polyvinyl acetate phthalate, celluloseacetate trimellitate, hydroxypropylmethylcellulose phthalate and lowpermeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride.
 18. Theformulation of claim 1 wherein the water low permeable polymer in thecoating is selected from ethylcellulose, hydroxypropylmethylcellulosephthalate and low permeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride.
 19. Theformulation of claim 1 wherein the combinations of water high permeableand water low permeable polymers is selected from:hydroxypropylmethylcellulose and hydroxypropylmethylcellulose phthalate,hydroxypropylcellulose and hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose and ethylcellulose, hydroxypropylcelluloseand ethylcellulose, hydroxypropylmethylcellulose and polyvinyl acetatephthalate, hydroxypropylcellulose and polyvinyl acetate phthalate, highpermeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride and lowpermeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride.
 20. Theformulation of claim 1 wherein the combination of water high permeableand water low permeable polymers is selected from the followingcombinations: hydroxypropylmethylcellulose andhydroxypropylmethylcellulose phthalate, hydroxypropylcellulose andethylcellulose, hydroxypropylmethylcellulose and ethylcellulose, highpermeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride and lowpermeable poly(ethylacrylate,methylmethacrylate)trimethylammoniumethylmethacrylate chloride.
 21. Theformulation of claim 1 wherein the ratio between the water highpermeable and the water low permeable polymer in the coating is from10:1 to 1:5.
 22. The formulation of claim 1 wherein the ratio betweenthe water high permeable and the water low permeable polymers in thecoating is from 3:1 to 1:3
 23. The formulation of claim 1 wherein thecoating represents 1 to 15 wt. % of the total weight of the formulation.24. The formulation of claim 1 wherein the coating further comprises aplasticizer selected from the group consisting of acetyl tributylcitrate, acetyl thriethyl citrate, acetylated fatty acid glycerides,castor oil, dibutyl phthalate, diethyl phthalate, diethyl sebacate,dibutyl sebacate, dimethyl phthalate, glycerol, glycerol monostearate,glycelyl triacetate, polyethylene glycols,polyoxyethylene/polyoxypropylene copolymers, propylene glycol, tributylcitrate, triethyl citrate.
 25. The formulation of claim 24 wherein theplasticizer is triethyl citrate.
 26. A process for the preparation of asolid controlled release pharmaceutical formulation comprising the stepsof: dissolving venlafaxine and polyvinylpyrrolidone in an organicsolvent, applying the resulting solution onto low viscosity polymer,homogeneously mixing the obtained granulate with a high viscositypolymer, and compressing the granulate to obtain a core which is thencoated with a polymeric coating comprising a water high permeablepolymer and a water low permeable polymer.
 27. The process of claim 26wherein venlafaxine in amorphous or in polymorphous form is dissolved inan organic solvent.
 28. The process of claim 27 wherein the organicsolvent is selected from the group consisting of ethanol, methanol,isopropyl alcohol, n-butyl alcohol, acetone, diethyl ether, ethylacetate, isopropyl acetate, methyl acetate, dichloromethane, chloroformand mixtures thereof.
 29. The process of claim 28 wherein the organicsolvent is ethanol.
 30. The process of claim 26 wherein the film coatingis applied from organic solvent or aqueous media. 31-37. (canceled)